MALE HYPOGONADISM

Todd W Frieze, MD, FACP, FACE, ECNU, CCDEndocrine Care Center

Notes about handout vs. lecture

There are more slides included in handout than will be covered in the lecture, thus more reference information in this handout

Slides which have been omitted in the lecture are marked in left lower corner with an “X”

Slides which have been modified for the lecture are marked in left lower corner with an “M”

Definition of Hypogonadism

Decrease in either or both of the two major functions of the testes: Sperm production, Testosterone (T) production

“Hypogonadism in men is a clinical syndrome that results from failure of the testis to produce physiologic levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of one or more levels of the hypothalamic-pituitary-testicular axis” – TES CPG

Prevalence of Hypogonadism

13.8 million men with hypogonadism Baltimore Longitudinal Study of Aging Only 9% treated

91% untreated

9% treated

Hypothalamic-Pituitary-

Gonadal Axis Hypothalamus: pulsatile GnRH

secretion Pituitary: pulsatile FSH and LH

secretion LH stimulates Leydig cells to

produce T FSH acts on Sertoli cells to

stimulate spermatogenesis (-) feedback via T and Inhibin B

T Synthesis

Similar to other adrenal hormones

Cholesterol is first key precursor

Requires several enzymatic steps

Other androgens produced en route

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T Metabolism Dihydrotestosterone

(DHT) has > affinity than T at androgen receptor (AR)

5-reductase: prostate, skin, reproductive tissues

Aromatase: adipose, liver, certain CNS nuclei

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Diurnal Circadian Rhythm

Peak levels in early a.m.

Night/swing shift different

Lost with aging

Wide inter-individual variation

Effects of Aging on T Levels

1-2% T levels per year after age 30

Gradual/more subtle loss than ♀

Free > total Individual variability Chronic disease

T Circulation

1-2% unbound or free 54-68% loosely bound to

other proteins e.g. albumin 30-44% tightly bound to sex

hormone binding globulin (SHBG)

Acts directly on target cells or converted to dihydrotestosterone (DHT) via 5-reductase or estradiol via aromatase

Total

T

SHBG

Albumin

2% Free

Bio-Available

T

Biologic Effects:Reproductive

Testes, penis, epididymis, seminal vesicles, and prostate: Stimulate prenatal differentiation Stimulate pubertal development Maintenance in adults

prostate size and PSA in hypogonadal ♂ Initiation and maintenance of spermatogenesis Stimulation and maintenance of sexual function

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Biologic Effects:Reproductive

DHT-dependent masculinization: Enlargement of external male genitalia Prostate enlargement

T-dependent processes: Male pattern hair growth Muscle mass Voice deepening

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Biologic Effects:Musculoskeletal

Muscle: nitrogen retention, lean body mass (LBM), and

body weight Anabolic cannot be dissociated from androgenic

properties Bone:

Stimulate proliferation of bone cells Estrogen effects > androgen (conversion)

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Biologic Effects:Skin and Hair

Sebum production is androgen-dependent (DHT > T)

Hair growth depends on androgens: Higher concentrations for face, chest, and upper

pubic area Lower concentrations for axilla and lower pubic

area

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Biologic Effects:Cardiovascular

Cardiac: Hypogonadal ♂ > risk CAD than eugonadal ? vasodilatory effects on coronary vessels

Altered lipid levels vs. pre-menopausal ♀: Lower HDL-C Higher triglycerides, LDL-C, VLDL-C May reflect reason for CAD risk

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Biologic Effects:Hepatic

Increased synthesisClotting factors

Triglyceride lipaseSialic acid

1-antitrypsinHaptoglobin

Decreased productionSHBG

Hormone-binding globulins

TransferrinFibrinogen

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Biologic Effects

Metabolic: Predisposes to insulin resistance Association w/ metabolic syndrome and DM 2

Hematologic: Stimulates erythropoietin production Alkylated androgens stimulate production of C1

esterase inhibitor Immune ?: > # of autoimmune diseases in ♀

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Clinical Presentation

Impaired T secretion varies based on age 1st trimester in utero depends on degree 3rd trimester in utero typically with normal ♂

sexual differentiation with micropenis Incomplete puberty otherwise

Impaired spermatogenesis: Infertility testicular size

Prepubertal Presentation Eunuchoid appearance

Crown to pubis length < pubis to floor length Arm span > height

Long bones grow out of proportion to axial skeleton under the influence of IGF-1

Small testis Decreased hair Small penis

Most common diagnosis is Klinefelter’s

Postpubertal PresentationPhysical/Metabolic

Decreased bone mineral densityDecreased muscle mass & strengthGynecomastiaDecreased 2 sexual characteristicsFrailtyIncreased body fatFatigueInsulin resistance

PsychologicalDepressed moodDiminished energy, sense of vitality, or well-beingImpaired cognition and memory

LaboratoryAnemia (NCNC)Oligo/azoospermia

SexualDiminished libidoErectile dysfunctionDifficulty achieving orgasmDecreased erectionsInfertility

Primary Hypogonadism (1)

Gonadal defectsGenetic diseases (e.g.

Klinefelter’s)Anatomic defects (anorchia,

cryptorchidism)Toxin-mediatedMedication-relatedEnzyme defects

TesticularTrauma, torsion, tumors,

resectionOrchitis (e.g. Mumps)

Hormone resistanceAndrogen insensitivityLH insensitivity

Klinefelter’s Syndrome

1:1000 live births Testes:

Small Firm

Gynecomastia Eunuchoid Azoospermia 50% T levels

93% 47XXY7% mosaic (46XY/ 47XXY)

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Primary Hypogonadism (2)

Toxin-mediatedRadiationChemotherapy (esp.

alkylating agents)AlcoholRadioactive iodineEnvironmental

Medications Ketoconazole Spironolactone Cimetidine Phenytoin FlutamideCorticosteroids

Androgen Insensitivity

AKA “Testicular Feminization” X-linked recessive disorder Normal male karyotype 46,XY Defect in AR T resistance

failure to develop male characteristics dependent on testosterone, so phenotypic ♀

Incomplete form with some androgen effects

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Primary Hypogonadism (3)

Enzyme defects: CAH, 5-reductase Noonan syndrome (~ Turner’s phenotype) Autoimmune syndromes Sertoli-cell only syndrome Less common genetic defects: 47, XYY,

myotonic dystrophy

Central HypogonadismHypothalamic

Kallmann syndromeInfiltrative diseases“Eugonadal sick”FunctionalConstitutional delay

PituitarySellar massesHypopituitarism

TraumaIatrogenicInfarct/apoplexy

Hyperprolactinemia

Gonadotropin suppression: Gonadal steroids, GnRH analogs, chronic opiates

Hormonal Deficiencies Isolated GnRH:

Idiopathic Kallmann syndrome:

AD or X-linked recessive traitPrepubertal hypogonadism, anosmia,

midline defects, congenital deafness, cryptorchidism

Isolated LH = fertile eunuch syndrome Isolated FSH or LH/FSH -subunits

Combined/Dual HPT Axis Causes

HemochromatosisSickle cell disease

ThalassemiaGlucocorticoid treatment

Anabolic steroid use/abuseAlcoholism

Chronic disease: CKD, cirrhosis, HIV

Historical Points

Sexual development Phenotypic presentation Milestones

Etiologic Behavioral changes Chemo, XRT, EtOH, surgery, trauma Pituitary symptoms Anosmia

Physical Examination (1)

Age consistency important Descended testes w/o

hypospadias Tanner staging

20-25 mL = normal adult testes volume (orchidometer)

Adult penile length 4-7 cm flaccid 12-16 cm stretched flaccid

Question

What is the name of this measuring device?

OrchidometerX

Physical Examination (2)

Testicular masses Male musculature Hair distribution Gynecomastia

Seen in 1 > 2 hypogonadism Eunuchoid proportions (lower body > 2 cm

longer than upper body Regression of 2 sexual characteristics delayed

Conditions Warranting ScreeningSellar mass, radiation to or diseases of sella

Medications that affect T production or metabolism (e.g. opioids, glucocorticoids)

HIV-associated weight lossESRD on maintenance dialysis

InfertilityModerate to severe COPD

Osteoporosis or low-trauma fractureDM type 2

TES Diagnostic Algorithm

Bhasin S, et al. J Clin Endocrinol Metab 2010; 95: 2536-59.

Total T (TT) Measurement

Morning sampling given diurnal changes Repeat testing necessary

Crucial if abnormal, borderline, or inconsistent with clinical suspicion

Measure during healthy/non-ill state Labor-intensive assays more accurate &

sensitive (e.g. LC/MS) Generally, level < 200 ng/dL diagnostic

Free T (FT) Measurement

Useful if: Abnormal SHBG levels suspected Inconsistent or borderline TT levels

Calculated via SHBG and TT levels as free androgen index (www.issam.ch/freetesto.htm)

Equilibrium dialysis only reliable direct measurement (not analog displacement)

Lack of consensus on threshold parameters

T Assay Difficulties

Vary depending on age and presence of comorbid conditions

Vary with time of day Interference from other circulating steroids Vast majority of hospitals use total T assays

neither certified by CDCP testosterone standardization program nor calibrated to NIST or CAP standards1

1. Bhasin S. J Clin Endocrinol Metab 2016; 101(3); 827-836.

SHBG Levels

ElevatedAdvancing age*HyperthyroidismCirrhosis*Estrogen excess/useHIV infectionAnticonvulsants*Levothyroxine use

DecreasedObesity*HypothyroidismAcromegalyNephrotic syndrome*Androgenic steroid, progestin,

or glucocorticoid use*Insulin resistanceCachexia/malnutrition

Take-Home Points

Morning levels (7-10 a.m.) Multiple samples needed Repeat if abnormal or discrepant Full panel testing often necessary:

Obesity SHBG TT/normal FT level age SHBG normal TT/ FT level

Use reliable reference laboratory/assays

FSH/LH (Gonadotropin) Levels

Supranormal levels = primary disease (Inappropriately) normal or low levels = central FSH has longer T½ so more accurate Consider LH only, unless fertility concerns Spermatogenic problems FSH with

normal LH and T levels but sperm counts Prolactin pulse frequency of both

Other Endocrine Tests

Prolactin and TSH in ~ 100% Estradiol and/or hCG levels:

Gynecomastia present Testicular tumor suspected

Karyotyping if suspect Klinefelter’s Anterior pituitary function if central process

MRI Sella

Perform if … Other pituitary hormone abnormalities/hypopituitarism Persistent hyperprolactinemia Tumor effects (headache, visual field change)

Finding mass lesion more likely if younger and lower T level T < 250 ng/dL for younger male T < 150 ng/dL for older male

Ancillary Testing

CBC (H/H) and PSA – see later Semen analysis if infertility concerns Systemic disease-specific tests e.g. iron Testicular ultrasound for mass/hydrocele Mammogram/breast ultrasound for mass BMD assessment via DXA after 1-2 yrs Sleep apnea evaluation, if symptoms

Diagnosis & Evaluation:TES CPG 2010

No widespread screening Screening questionnaires not recommended Morning TT by reliable assay with repeat Measure FT or BT, using accurate & reliable

assay, if borderline TT or SHBG alteration Do not measure during acute/subacute illness

Bhasin S, et al. J Clin Endocrinol Metab 2010; 95: 2536-59.

Golden Rules for Diagnosis

Use accurate assays, CDC-certified lab, and rigorously-derived reference range

Do NOT diagnose based on single T level Do NOT diagnose based only on T level Measure free T using an accurate method

when suspect binding protein abnormality Use ancillary data (testicular volume, FSH/LH

levels) to aid in diagnosis

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Bone Mineral Density

3-6% of ♂ >50 have osteoporosis 28-47% of ♂ >50 have osteopenia Risk of fracture 22% for ♂ >60 risk with aging occurs 7-10 years after ♀ with age correlates with estradiol > T levels Insights from conversion enzyme deficiencies:

Estradiol > T to prevent bone resorption Estradiol = T for bone formation

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Treatment of Hypogonadism

Clear and widely recommended that patients with primary or secondary hypogonadism, presenting with symptoms, should be treated with testosterone replacement therapy (TRT)

Neither long-term benefits or risks established in middle-aged/older males with age-related decline in T levels

3 month trial if borderline levels/symptoms

Potential Benefits of TRT

Restores libido and erectile function Produces &/or maintains virilization Increases energy and improves mood Improves body composition

fat mass, lean body mass & muscle strength Stabilizes or increases bone density

Benefits in young >> elderly hypogonadal ♂

Specific Points

Improvement in libido has a low threshold without dose effect based on T level obtained

Erectile function improved with libido if no concomitant neuro/vascular disease

TTrials: inaugural report just published1

Modest, waning improvement in sexual function but less than PDE5-I treatments

Limited physical function and psychologic benefits

1. Synder PJ, et al. N Engl J Med, 2016; 374(7): 611-624.

Contraindications

Clinical prostate cancer, unexplained PSA or prostate abnormality, BPH w/severe LUTS

Male breast cancer or Prolactinoma Erythrocytosis (Hct >50%) Family/personal history of VTE/thrombophilia Class III or IV CHF Undiagnosed/untreated sleep apnea or edema MI or CVA within last 6 months

Testosterone Formulations(All schedule III drugs due to abuse potential)

Formulation Dosage and FrequencyInjectable

Cypionate/enanthate 50-400 mg every 1-4 weeksUndecanoate 750 mg baseline, @4 wks, then q10 wks

TopicalPatch system 2-8 mg dailyGel (upper body) 12.5-100 mg dailyGel (thigh) 10-70 mg dailyAxillary solution 30-120 mg daily

Testosterone pellets 2-6 pellets implanted SC q 3-6 moBuccal system 30 mg every 12 hrsNasal gel application 5.5 mg each nostril TID (total 33 mg)

Formulations: Pros & Cons (1)Type Pros ConsInjectable Inexpensive Peak/trough issuescypionate, Effective symptom relief Risk polycythemiaenanthate ? Decrease HDL

IM injections, ? Painfulundecanoate Ultra long-acting Expensive

~ AEs to aboveTransdermal T levels mimic circadian rhythm Moderate cost

patch Low incidence of polycythemia Visible, not discreteDifficulty achieving

adequate T levelsSkin irritationLack of adhesivenessDaily administration

T Undecanoate

Int’l approval 12 yrs; NDA 8/07 approval 3/14 Efficacy proven – 94% Consistent post-injection reactions:

Pulmonary oil microembolism (POME) due to castor oil Anaphylaxis due to castor oil or benzyl benzoate No deaths, but resuscitations and hospitalizations

REMS program for prescribers/clinics

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Formulations: Pros & Cons (2)Type Pros ConsTransdermal T levels maintained over Expensive

gel/liquid 24-hr period Transference concernsHigh patient compliance Drug accumulation

Variable absorptionMessySkin irritationDaily administration

Pellets Longest duration of action Procedural implantationLocal side effects, extrusion

Buccal system Physiologic range levels Expensive, oral irritation, altered taste, BID dosing

Nasal gel Convenient, quick Rhinorrhea, epistaxis, nasal Minimal transference risk discomfort, URT infections

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Oral T Agents

17-methyl testosterone not recommended 1st pass effects risk hepatotoxicity Potential liver toxicity, including neoplasms Dyslipidemia via HDL and LDL

Oral testosterone undecanoate* Bypasses first pass metabolism No adverse hepatic side effects Not available in U.S.

Sept 18th – FDA advisory panel votes against 18-3

* Not available in U.S.

Potential Class Adverse EffectsAdverse Effect CommentProstate cancer Controversial; no conclusive evidenceBenign prostatic hyperplasia Infrequently worsened in mild or

moderate LUTS; avoid if severe LUTSTesticular atrophy or infertility Common, especially in young men;

usually reversible when treatment stopsSleep apnea Infrequent; controversialAcne and oily skin InfrequentGynecomastia InfrequentFluid retention/edema Rarely of clinical significance; concern if

class III or IV CHF, CKD, or cirrhosisErythrocytosis Injectable >> Transdermal/otherHypertension Infrequent, injectable > others

Adverse Events with TRT

Evidence of Association Acne, oiliness of skin Erythrocytosis Testicular atrophy,

infertility risk of detection of

prostate events growth of metastatic

prostate cancer Formulation-specific

Gynecomastia Prostate cancer Obstructive sleep apnea Lower urinary tract

symptoms (LUTS) Cardiovascular events

Weak or Inconclusive Evidence of Association

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Topical Label Change Reports of secondary T exposure in children Adverse events: inappropriate genitalia

enlargement, premature pubarche, advanced bone age, increased libido, aggressive behavior

Boxed warning label change for topical therapies Precautions suggested to minimize potential for

secondary exposure Wash hands thoroughly after exposure Avoid skin contact until dried completely Keep application site covered

http://www.FDA.gov/NewsEvents/Newsroom/PressAnnouncements/ucm149580.htmM

General Label Updates

Risk of venous thromboembolism (VTE) Previous labeled as erythrocytosis consequence Thrombosis warning added to label of all products Inquire about personal/family VTE history before But, NO routine thrombophilia screening suggested

Spring 2015: TRT use limited to ♂ who have low T levels in conjunction with an associated medical condition

Cardiovascular Risk (1)

Epidemiologic studies suggest hypogonadism a/w CV events and all-cause mortality

TRT favorably changes many CV risk factors To date, no RCTs to evaluate CV risk concern Recent published studies raised concerns

Retrospective with “diseased” males Important methodologic limitations

CV Risks of TRTBiological Plausibility: Consistent Evidence

Potential CV Risks Hematocrit HDL cholesterol Platelet aggregation Sodium retention Smooth muscle

proliferation VCAM expression

Potential CV Benefits Vasodilator effect –

increased coronary and penile blood flow

whole body fat (visceral and subcutaneous)

Vascular reactivity Shortened QTc interval

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Mixed Results from Recent Studies on TRT and CVD

Retrospective analyses with conflicting results Limitations

Heterogeneity of study populations, intervention duration, and study designs

Variable definitions & ascertainment of CV outcomes Unclear treatment indications, treatment regimens, T

levels, and exposure Residual confounding: study groups differed on CV

risk factors

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Cardiovascular Risk (2)

9/14 FDA: need further studies to evaluate CV risk associated with TRT

Injectable TRT show greater MI and stroke risk1

AACE/ACE Position Statement affirms all points2

TEAAM: no significant difference in CV risk using CIMT and CAC3

TEAAM and TTrials4: not powered for CV events

1. Layton JL, et al. JAMA intern Med, 2015; e-pub ahead of print2. Goodman N, et al. Endocr Pract, 2015; 21(9): 1066-10733. Basaria S, et al. JAMA, 2015; 314(6): 570-5814. Synder PJ, et al. N Engl J Med, 2016; 374(7): 611-624.

Take-Home Points about TRT

Thorough diagnostic work-up necessary Cautious approach to TRT in elderly/aging ♂ Inform patients that long-term risks not known

with possibility that TRT may be harmful Although cost may be lower, “older” injectable

preparations are NOT easier to use and have increased risks of side effects vs. others

Monitoring

Evaluate symptom response 3-6 months after start, then each clinic visit

If 1 hypogonadism, follow LH levels H/H:

Baseline, 3-6 months, then annually If Hct >54%, stop tx and re-evaluate

BMD measurement via DXA after 1-2 yrs Adverse effects at each visit

Assessing Response to T T levels at 2-3 months after initiation Aim to raise to mid-normal range

Injectable cypionate/enanthate Midway b/w injections, then peak/troughInjectable undecanoate Just prior to next injectionTransdermal patches 3-12 hours after applicationBuccal system Immediately before fresh applicationTransdermal gels/liquid After use for at least 1 week,

At least 2 hours after applicationTestosterone pellets At end of dosing intervalNasal gel application Not labeled at presentOral undecanoate* 3-5 hours after ingestion

* Not available in U.S.

Monitoring: Prostate Issues

Men > 40 yrs DRE/PSA @ baseline, 3-6 months, then per CPGs Prostate symptom assessment

Urology consultation/biopsy if: Abnormal baseline DRE or PSA > 4.0 ng/mL PSA > 1.4 ng/mL in 12-month period PSA velocity > 0.4 ng/mL/yr after 6 month tx AUA/IPSS score >19

Other Therapies

Clomiphene citrate for secondary disease* Recent study completion with 79% T normalization

as main goal Non-inferiority for sperm count Well-tolerated

Anti-estrogens not recommended/routinely used

* Not approved to date in U.S.

Gonadotropin or GnRH Therapy

Only for secondary disease Initiate and maintain spermatogenesis for

fertility purposes hCG (~LH) +/- hMG (~FSH) GnRH via pump Monitor gonadotropins, T levels, and semen

analyses